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Reference Guide on Toxicology bernard d. GoldsTein and mary sue henifin Bernard D. Goldstein, M.D., is Professor of Environmental and Occupational Health and Former Dean, Graduate School of Public Health, University of Pittsburgh. Mary Sue Henifin, J.D., M.P.H., is a Partner with Buchanan Ingersoll, P.C., Princeton, New Jersey. ConTenTs I. Introduction, 635 A. Toxicology and the Law, 637 B. Purpose of the Reference Guide on Toxicology, 639 C. Toxicological Study Design, 639 1. In vivo research, 640 2. In vitro research, 645 D. Extrapolation from Animal and Cell Research to Humans, 646 E. Safety and Risk Assessment, 646 1. The use of toxicological information in risk assessment, 650 F. Toxicological Processes and Target Organ Toxicity, 651 G. Toxicology and Exposure Assessment, 656 H. Toxicology and Epidemiology, 657 II. Demonstrating an Association Between Exposure and Risk of Disease, 660 A. On What Species of Animals Was the Compound Tested? What Is Known About the Biological Similarities and Differences Between the Test Animals and Humans? How Do These Similarities and Differences Affect the Extrapolation from Animal Data in Assessing the Risk to Humans? 661 B. Does Research Show That the Compound Affects a Specific Target Organ? Will Humans Be Affected Similarly? 662 C. What Is Known About the Chemical Structure of the Compound and Its Relationship to Toxicity? 663 D. Has the Compound Been the Subject of In Vitro Research, and if So, Can the Findings Be Related to What Occurs In Vivo? 664 E. Is the Association Between Exposure and Disease Biologically Plausible? 664 633

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Reference Manual on Scientific Evidence III. Specific Causal Association Between an Individual’s Exposure and the Onset of Disease, 665 A. Was the Plaintiff Exposed to the Substance, and if So, Did the Exposure Occur in a Manner That Can Result in Absorption into the Body? 666 B. Were Other Factors Present That Can Affect the Distribution of the Compound Within the Body? 667 C. What Is Known About How Metabolism in the Human Body Alters the Toxic Effects of the Compound? 668 D. What Excretory Route Does the Compound Take, and How Does This Affect Its Toxicity? 668 E. Does the Temporal Relationship Between Exposure and the Onset of Disease Support or Contradict Causation? 668 F. If Exposure to the Substance Is Associated with the Disease, Is There a No Observable Effect, or Threshold, Level, and if So, Was the Individual Exposed Above the No Observable Effect Level? 669 IV. Medical History, 670 A. Is the Medical History of the Individual Consistent with the Toxicologist’s Expert Opinion Concerning the Injury? 670 B. Are the Complaints Specific or Nonspecific? 671 C. Do Laboratory Tests Indicate Exposure to the Compound? 672 D. What Other Causes Could Lead to the Given Complaint? 672 E. Is There Evidence of Interaction with Other Chemicals? 673 F. Do Humans Differ in the Extent of Susceptibility to the Particular Compound in Question? Are These Differences Relevant in This Case? 674 G. Has the Expert Considered Data That Contradict His or Her Opinion? 674 V. Expert Qualifications, 675 A. Does the Proposed Expert Have an Advanced Degree in Toxicology, Pharmacology, or a Related Field? If the Expert Is a Physician, Is He or She Board Certified in a Field Such as Occupational Medicine? 675 B. Has the Proposed Expert Been Certified by the American Board of Toxicology, Inc., or Does He or She Belong to a Professional Organization, Such as the Academy of Toxicological Sciences or the Society of Toxicology? 677 C. What Other Criteria Does the Proposed Expert Meet? 678 VI. Acknowledgments, 679 Glossary of Terms, 680 References on Toxicology, 685 634

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Reference Guide on Toxicology I. Introduction The discipline of toxicology is primarily concerned with identifying and under- standing the adverse effects of external chemical and physical agents on biological systems. The interface of the evidence from toxicological science with toxic torts can be complex, in part reflecting the inherent challenges of bringing science into a courtroom, but also because of issues particularly pertinent to toxicology. For the most part, toxicological study begins with a chemical or physical agent and asks what impact it will have, while toxic tort cases begin with an individual or a group that has suffered an adverse impact and makes claims about its cause. A particular challenge is that only rarely is the adverse impact highly specific to the toxic agent; for example, the relatively rare lung cancer known as mesothelioma is almost always caused by asbestos. The more common form of lung cancer, bronchial carcinoma, also can be caused by asbestos, but asbestos is a relatively uncommon cause compared with smoking, radon, and other known causes of lung cancer.1 Lung cancer itself is unusual in that for the vast majority of cases, we can point to a known cause—smoking. However, for many diseases, there are few if any known causes, for example, pancreatic cancer. Even when there are known causes of a disease, most individual cases are often not ascribable to any of the known causes, such as with leukemia. In general, there are only a limited number of ways that biological tissues can respond, and there are many causes for each response. Accordingly, the role of toxicology in toxic tort cases often is to provide information that helps evalu- ate the causal probability that an adverse event with potentially many causes is caused by a specific agent. Similarly, toxicology is commonly used as a basis for regulating chemicals, depending upon their potential for effect. Assertions related to the toxicological predictability of an adverse consequence in relation to the stringency of the regulatory law are not uncommon bases for legal actions against regulatory agencies. Identifying cause-and-effect relationships in toxicology can be relatively straightforward; for example, when placed on the skin, concentrated sulfuric acid will cause massive tissue destruction, and carbon monoxide poisoning is identifi- able by the extent to which carbon monoxide is attached to the oxygen-carrying portion of blood hemoglobin, thereby decreasing oxygen availability to the body. But even these two seemingly straightforward examples serve to illustrate the complexity of toxicology and particularly its emphasis on understanding dose– response relationships. The tissue damage caused by sulfuric acid is not specific to this chemical, and at lower doses, no effect will be seen. Carbon monoxide is not only an external poison but is a product of normal internal metabolism such 1. Contrast this issue with the relatively straightforward situation in infectious disease in which the disease name identifies the cause; for example, cholera is caused by Vibrio cholerae, tuberculosis by the Mycobacterium tuberculosis, HIV-AIDs by the HIV virus, and so on. 635

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Reference Manual on Scientific Evidence that about 1 out of 200 hemoglobin molecules will normally have carbon mon- oxide attached, and this can increase depending upon concomitant disease states. Furthermore, the complex temporal relation governing the uptake and release of carbon monoxide from hemoglobin also must be considered in assessing the extent to which an adverse impact may be ascribable to carbon monoxide exposure. Thus the diagnosis of carbon monoxide poisoning requires far more information than the simple presence of detectable carbon monoxide in the blood. Complexity in toxicology is derived primarily from three factors. The first is that chemicals often change within the body as they go through various routes to eventual elimination.2 Thus absorption, distribution, metabolism, and excre- tion are central to understanding the toxicology of an agent. The second is that human sensitivity to chemical and physical agents can vary greatly among indi- viduals, often as a result of differences in absorption, distribution, metabolism, or excretion, as well as target organ sensitivity—all of which can be genetically determined. The third major source of complexity is the need for extrapolation, either across species, because much toxicological data are obtained from studies in laboratory animals, or across doses, because human toxicological and epide- miological data often are limited to specific dose ranges that differ from the dose suffered by a plaintiff alleging a toxic tort impact. All three of these factors are responsible for much of the complexity in utilizing toxicology for tort or regula- tory judicial decisions and are described in more detail below. Classically, toxicology is known as the science of poisons. It is the study of the adverse effects of chemical and physical agents on living organisms.3 Although it is an age-old science, toxicology has only recently become a discipline distinct from pharmacology, biochemistry, cell biology, and related fields. There are three central tenets of toxicology. First, “the dose makes the poison”; this implies that all chemical agents are intrinsically hazardous—whether they cause harm is only a question of dose.4 Even water, if consumed in large quantities, can be toxic. Second, each chemical or physical agent tends to pro- duce a specific pattern of biological effects that can be used to establish disease 2. Direct-acting toxic agents are those whose toxicity is due to the parent chemical entering the body. A change in chemical structure through metabolism usually results in detoxification. Indirect- acting chemicals are those that must first be metabolized to a harmful intermediate for toxicity to occur. For an overview of metabolism in toxicology, see R.A. Kemper et al., Metabolism: A Determinant of Toxicity, in Principles and Methods of Toxicology 103–178 (A. Wallace Hayes ed., 5th ed. 2008). 3. Casarett and Doull’s Toxicology: The Basic Science of Poisons 13 (Curtis D. Klaassen ed., 7th ed. 2007). 4. A discussion of more modern formulations of this principle, which was articulated by Paracelsus in the sixteenth century, can be found in David L. Eaton, Scientific Judgment and Toxic Torts— A Primer in Toxicology for Judges and Lawyers, 12 J.L. & Pol’y 5, 15 (2003); Ellen K. Silbergeld, The Role of Toxicology in Causation: A Scientific Perspective, 1 Cts. Health Sci. & L. 374, 378 (1991). A short review of the field of toxicology can be found in Curtis D. Klaassen, Principles of Toxicology and Treatment of Poisoning, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics 1739 (11th ed. 2008). 636

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Reference Guide on Toxicology causation.5 Third, the toxic responses in laboratory animals are useful predictors of toxic responses in humans. Each of these tenets, and their exceptions, is discussed in greater detail in this reference guide. The science of toxicology attempts to determine at what doses foreign agents produce their effects. The foreign agents classically of interest to toxicologists are all chemicals (including foods and drugs) and physical agents in the form of radia- tion, but not living organisms that cause infectious diseases.6 The discipline of toxicology provides scientific information relevant to the following questions: 1. What hazards does a chemical or physical agent present to human popula- tions or the environment? 2. What degree of risk is associated with chemical exposure at any given dose?7 Toxicological studies, by themselves, rarely offer direct evidence that a disease in any one individual was caused by a chemical exposure.8 However, toxicology can provide scientific information regarding the increased risk of contracting a disease at any given dose and help rule out other risk factors for the disease. Toxi- cological evidence also contributes to the weight of evidence supporting causal inferences by explaining how a chemical causes a specific disease through describ- ing metabolic, cellular, and other physiological effects of exposure. A. Toxicology and the Law The growing concern about chemical causation of disease is reflected in the public attention devoted to lawsuits alleging toxic torts, as well as in litigation concerning the many federal and state regulations related to the release of potentially toxic compounds into the environment. Toxicological evidence frequently is offered in two types of litigation: tort and regulatory. In tort litigation, toxicologists offer evidence that either supports 5. Some substances, such as central nervous system toxicants, can produce complex and non- specific symptoms, such as headaches, nausea, and fatigue. 6. Forensic toxicology, a subset of toxicology generally concerned with criminal matters, is not addressed in this reference guide, because it is a highly specialized field with its own literature and methodologies that do not relate directly to toxic tort or regulatory issues. 7. In standard risk assessment terminology, hazard is an intrinsic property of a chemical or physi- cal agent, while risk is dependent both upon hazard and on the extent of exposure. Note that this first “law” of toxicology is particularly pertinent to questions of specific causation, while the second “law” of toxicology, the specificity of effect, is pertinent to questions of general causation. 8. There are exceptions, for example, when measurements of levels in the blood or other body constituents of the potentially offending agent are at a high enough level to be consistent with reason- ably specific health impacts, such as in carbon monoxide poisoning. 637

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Reference Manual on Scientific Evidence or refutes plaintiffs’ claims that their diseases or injuries were caused by chemi- cal exposures.9 In regulatory litigation, toxicological evidence is used to either support or challenge government regulations concerning a chemical or a class of chemicals. In regulatory litigation, toxicological evidence addresses the issue of how exposure affects populations10 rather than addressing specific causation, and agency determinations are usually subject to the court’s deference.11 Dose is a central concept in the field of toxicology, and an expert toxicolo- gist will consider the extent of a plaintiff’s dose in making an opinion.12 But dose has not been a central issue in many of the most important judicial deci- sions concerning the relation of toxicological evidence to toxic tort decisions. These have mostly been general causation issues: For example, is a silicon breast implant capable of causing rheumatoid arthritis, or is Bendectin capable of causing deformed babies.13 However, in most specific causation issues involving exposure to a chemical known to be able to cause the observed effect, the primary issue will be whether there has been exposure to a sufficient dose to be a likely cause of this effect. 9. See, e.g., Gen. Elec. Co. v. Joiner, 522 U.S. 136 (1997); Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579 (1993). Courts have held that toxicologists can testify as to disease causation related to chemical exposures. See, e.g., Bonner v. ISP Techs, Inc., 259 F.3d 924, 928–31 (8th Cir. 2001); Paoli R.R. v. Monsanto Co., 915 F.2d 829 (3d Cir. 1990); Loudermill v. Dow Chem. Co., 863 F.2d 566, 569–70 (8th Cir. 1988). 10. Again, there are exceptions. For example, certain regulatory approaches, such as the control of hazardous air pollutants, are based on the potential impact to a putative maximally exposed indi- vidual rather than to the general population. 11. See, e.g., Int’l Union, United Mine Workers of Am. v. U.S. Dep’t of Labor, 358 F.3d 40, 43–44 (D.C. Cir. 2004) (determinations by Secretary of Labor are given deference by the court, but must be supported by some evidence, and cannot be capricious or arbitrary); N.M. Mining Ass’n v. N.M. Water Quality Control Comm., 150 P.3d 991, 995–96 (N.M. Ct. App. 2006) (action by a gov- ernment agency is presumptively valid and will be given deference by the court. The court will only overturn a regulatory decision if it is capricious and arbitrary, or not supported by substantial evidence). 12. Dose is a function of both concentration and duration. Haber’s rule is a century-old simpli- fied expression of dose effects in which the effect of a concentration and duration of exposure is a constant (e.g., exposure to an agent at 10 parts per million for 1 hour has the same impact as exposure to 1 part per million for 10 hours). Exposure levels, which are concentrations, are often confused with dose. This can be particularly problematic when attempting to understand the implications of exposure to a level that exceeds a regulatory standard that is set for a different time frame. For example, assume a drinking water contaminant is a known cause of cancer. To avoid a 1 in 100,000 lifetime risk caused by this contaminant in drinking water, and assuming that the average person will drink approximately 2000 mL of water daily for a lifetime, the regulatory authority sets the allowable contaminant standard in drinking water at 10 µg/L. Drinking one glass of water containing 20 µg/L of this contaminant, although exceeding the standard, does not come close to achieving a “reasonably medically probable” cause of an individual case of cancer. 13. See, e.g., In re Silicone Gel Breast Implants Prods. Liab. Litig., 318 F. Supp. 2d 879, 891 (C.D. Cal. 2004); Joseph Sanders, From Science to Evidence: The Testimony on Causation in the Bendectin Cases, 46 Stan. L. Rev. 1, 19 (1993). 638

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Reference Guide on Toxicology B. Purpose of the Reference Guide on Toxicology This reference guide focuses on the scientific issues that arise most frequently in toxic tort cases. Where it is appropriate, the guide explores the use of regula- tory data and how the courts treat such data. It also provides an overview of the basic principles and methodologies of toxicology and offers a scientific context for proffered expert opinion based on toxicological data.14 The reference guide describes research methods in toxicology and the relationship between toxicology and epidemiology, and it provides model questions for evaluating the admissibility and strength of an expert’s opinion. Following each question is an explanation of the type of toxicological data or information that is offered in response to the question, as well as a discussion of its significance. C. Toxicological Study Design Toxicological studies usually involve exposing laboratory animals (in vivo research) or cells or tissues (in vitro research) to chemical or physical agents, monitoring the outcomes (such as cellular abnormalities, tissue damage, organ toxicity, or tumor formation), and comparing the outcomes with those for unexposed control groups. As explained below,15 the extent to which animal and cell experiments accurately predict human responses to chemical exposures is subject to debate.16 However, because it is often unethical to experiment on humans by exposing them to known doses of chemical agents, animal toxicological evidence often provides the best scientific information about the risk of disease from a chemical exposure.17 In contrast to their exposure to drugs, only rarely are humans exposed to environmental chemicals in a manner that permits a quantitative determination of adverse outcomes.18 This area of toxicological study may consist of individual or multiple case reports, or even experimental studies in which individuals or groups of individuals have been exposed to a chemical under circumstances that permit analysis of dose–response relationships, mechanisms of action, or other aspects of 14. The use of toxicological evidence in regulatory decisionmaking is discussed in Casarett and Doull’s Toxicology: The Basic Science of Poisons, supra note 3, at 13–14; Barbara D. Beck et al., The Use of Toxicology in the Regulatory Process, in Principles and Methods of Toxicology, supra note 2, at 45–102. For a more general discussion of issues that arise in considering expert testimony, see Margaret A. Berger, The Admissibility of Expert Testimony, Section IV, in this manual. 15. See infra Section I.D. 16. The controversy over the use of toxicological evidence in tort cases is described in Bernard D. Goldstein, Toxic Torts: The Devil Is in the Dose, 16 J.L. & Pol’y 551 (2008); Joseph V. Rodricks, Evaluating Disease Causation in Humans Exposed to Toxic Substances, 14 J.L. & Pol’y 39 (2006); Silbergeld, supra note 4, at 378. 17. See, e.g., Office of Tech. Assessment, U.S. Congress, Reproductive Health Hazards in the Workplace 8 (1985). 18. However, it is from drug studies in which multiple animal species are compared directly with humans that many of the principles of toxicology have been developed. 639

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Reference Manual on Scientific Evidence toxicology. For example, individuals occupationally or environmentally exposed to polychlorinated biphenyls (PCBs) prior to prohibitions on their use have been studied to determine the routes of absorption, distribution, metabolism, and excre- tion for this chemical. Human exposure occurs most frequently in occupational settings where workers are exposed to industrial chemicals such as lead or asbestos; however, even under these circumstances, it is usually difficult, if not impossible, to quantify the amount of exposure. Moreover, human populations are exposed to many other chemicals and risk factors, making it difficult to isolate the increased risk of a disease that is the result of exposure to any one chemical.19 Toxicologists use a wide range of experimental techniques, depending in part on their area of specialization. Toxicological research may focus on classes of chemical compounds, such as solvents and metals; body system effects, such as neurotoxicology, reproductive toxicology, and immunotoxicology; and effects on physiological processes, including inhalation toxicology, dermatotoxicology, and molecular toxicology (the study of how chemicals interact with cell molecules). Each of these areas of research includes both in vivo and in vitro research.20 1. In vivo research Animal research in toxicology generally falls under two headings: safety assessment and classic laboratory science, with a continuum between them. As explained in Section I.E, safety assessment is a relatively formal approach in which a chemical’s potential for toxicity is tested in vivo or in vitro using standardized techniques often prescribed by regulatory agencies, such as the Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA).21 The roots of toxicology in the science of pharmacology are reflected in an emphasis on understanding the absorption, distribution, metabolism, and excretion of chemicals. Basic toxicological laboratory research also focuses on the mecha- nisms of action of external chemical and physical agents. Such research is based on the standard elements of scientific studies, including appropriate experimental design using control groups and statistical evaluation. In general, toxicological research attempts to hold all variables constant except for that of the chemical exposure.22 Any change in the experimental group not found in the control group is assumed to be perturbation caused by the chemical. 19. See, e.g., Office of Tech. Assessment, U.S. Congress, supra note 17, at 8. 20. See infra Sections I.C.1, I.C.2. 21. W.J. White et al., The Use of Laboratory Animals in Toxicology Research, in Principles and . W.J. Methods of Toxicology 1055–1102 (A. Wallace Hayes ed., 5th ed. 2008); M.A. Dorato et al., The Toxicologic Assessment of Pharmaceutical and Biotechnology Products, in Principles and Methods of Toxicol- ogy 325–68 (A. Wallace Hayes ed., 5th ed. 2008). 22. See generally Alan Poole & George B. Leslie, A Practical Approach to Toxicological Inves- tigations (1989); Principles and Methods of Toxicology (A. Wallace Hayes ed., 2d ed. 1989); see also discussion on acute, short-term, and long-term toxicity studies and acquisition of data in Frank C. Lu, Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment 77–92 (2d ed. 1991). 640

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Reference Guide on Toxicology a. Dose–response relationships An important component of toxicological research is dose–response relationships. Thus, most toxicological studies generally test a range of doses of the chemical. Animal experiments are conducted to determine the dose–response relationships of a compound by measuring how response varies with dose, including diligently searching for a dose that has no measurable physiological effect. This information is useful in understanding the mechanisms of toxicity and extrapolating data from animals to humans.23 b. Acute Toxicity Testing—Lethal Dose 50 To determine the dose–response relationship for a compound, a short-term lethal dose 50% (LD50) may be derived experimentally. The LD50 is the dose at which a compound kills 50% of laboratory animals within a period of days to weeks. The use of this easily measured end point for acute toxicity to a large extent has been replaced, in part because recent advances in toxicology have provided other pertinent end points, and in part because of pressure from animal rights activists to reduce or replace the use of animals in laboratory research.24 c. No observable effect level A dose–response study also permits the determination of another important char- acteristic of the biological action of a chemical—the no observable effect level (NOEL).25 The NOEL sometimes is called a threshold, because it is the level above which observable effects in test animals are believed to occur and below which no toxicity is observed.26 Of course, because the NOEL is dependent on the ability to 23. See infra Sections I.D, II.A. 24. Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council, Toxicity Testing in the 21st Century: A Vision and a Strategy (2007). 25. For example, undiluted acid on the skin can cause a horrible burn. As the acid is diluted to lower and lower concentrations, less and less of an effect occurs until there is a concentration suffi- ciently low (e.g., one drop in a bathtub of water, or a sample with less than the acidity of vinegar) that no effect occurs. This no observable effect concentration differs from person to person. For example, a baby’s skin is more sensitive than that of an adult, and skin that is irritated or broken responds to the effects of an acid at a lower concentration. However, the key point is that there is some concentration that is completely harmless to the skin. 26. The significance of the NOEL was relied on by the court in Graham v. Canadian National Railway Co., 749 F. Supp. 1300 (D. Vt. 1990), in granting judgment for the defendants. The court found the defendants’ expert, a medical toxicologist, persuasive. The expert testified that the plaintiffs’ injuries could not have been caused by herbicides, because their exposure was well below the reference dose, which he calculated by taking the NOEL and decreasing it by a safety factor to ensure no human effect. Id. at 1311–12 & n.11. But see Louderback v. Orkin Exterminating Co., 26 F. Supp. 2d 1298 (D. Kan. 1998) (failure to consider threshold levels of exposure does not necessarily render expert’s opinion unreliable where temporal relationship, scientific literature establishing an association between exposure and various symptoms, plaintiffs’ medical records and history of disease, and exposure to or 641

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Reference Manual on Scientific Evidence observe an effect, the level is sometimes lowered once more sophisticated methods of detection are developed. d. Benchmark dose For regulatory toxicology, the NOEL is being replaced by a more statistically robust approach known as the benchmark dose (BD). The BD is determined based on dose–response modeling and is defined as the exposure associated with a specified low incidence of risk, generally in the range of 1% to 10%, of a health effect, or the dose associated with a specified measure or change of a biological effect. To model the BD, sufficient data must exist, such as at least a statistically or biologically significant dose-related trend in the selected end point.27 e. No-threshold model and determination of cancer risk Certain genetic mutations, such as those leading to cancer and some inherited disorders, are believed to occur without any threshold. In theory, the cancer- causing mutation to the genetic material of the cell can be produced by any one molecule of certain chemicals. The no-threshold model led to the development of the one-hit theory of cancer risk, in which each molecule of a cancer-causing chemical has some finite possibility of producing the mutation that leads to cancer. (See Figure 1 for an idealized comparison of a no-threshold and threshold dose– response.) This risk is very small, because it is unlikely that any one molecule of a potentially cancer-causing agent will reach that one particular spot in a specific cell and result in the change that then eludes the body’s defenses and leads to a clinical case of cancer. However, the risk is not zero. The same model also can be used to predict the risk of inheritable mutational events.28 the presence of other disease-causing factors were all considered). See also DiPirro v. Bondo Corp., 62 Cal. Rptr. 3d 722, 750 (Cal. Ct. App. 2007) (judgment for the maker of auto touchup paint based on finding that there was substantial evidence in the record to show that the level of a particular toxin [toluene] present in the paint fell 1000 times below the NOEL of that toxin and therefore no warning label needed on paint can). 27. See S. Sand et al., The Current State of Knowledge on the Use of the Benchmark Dose Concept in Risk Assessment, 28 J. Appl. Toxicol. 405–21 (2008); W. Slob et al., A Statistical Evaluation of Toxicity Study Designs for the Estimation of the Benchmark Dose in Continuous Endpoints, 84 Toxicol. Sci. 167–85 (2005). Courts also recognize the benchmark dose. See, e.g., Am. Forest & Paper Ass’n Inc. v. EPA, 294 F.3d 113, 121 (D.C. Cir. 2002) (EPA’s use of benchmark dose takes into account comprehensive dose–response information unlike NOEL and thus its use was not arbitrary in determining that metha- nol should remain on the list of hazardous air pollutants); California v. Tri-Union Seafoods, LLC, 2006 WL 1544384 (Cal. Super. Ct. May 11, 2006) (benchmark dose should not be equated with LOEL (lowest observable effect level) and thus toxicologist’s testimony regarding methylmercury in tuna was unreliable for purposes of California’s Proposition 65). 28. For further discussion of the no-threshold model of carcinogenesis, see James E. Klaunig & Lisa M. Kamendulis, Chemical Carcinogens, in Casarett and Doull’s Toxicology: The Basic Science of Poisons, supra note 3, at 329. But see V.P. Bond et al., Current Misinterpretations of the Linear No-Threshold 642

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Reference Guide on Toxicology Figure 1. Idealized comparison of a no-threshold and threshold dose–response relationship. Hypothesis, 70 Health Physics 877 (1996); Marvin Goldman, Cancer Risk of Low-Level Exposure, 271 Science 1821 (1996). Although the one-hit model explains the response to most carcinogens, there is accumulating evidence that for certain cancers there is in fact a multistage process and that some cancer-causing agents, so-called epigenetic or nongenotoxic agents, act through nonmutational processes, Commit- tee on Risk Assessment Methodology, National Research Council, Issues in Risk Assessment 34–35, 187, 198–201 (1993). For example, the multistage cancer process may explain the carcinogenicity of 11-1 xed image benzo[a]pyrene (produced by the combustion of hydrocarbons such as oil) and chlordane (a termite pesticide). However, nonmutational responses to asbestos, dioxin, and estradiol cause their carcino- genic effects. The appropriate mathematical model to use to depict the dose–response relationship for such carcinogens is still a matter of debate. Id. at 197–201. Proposals have been made to merge cancer and noncancer risk assessment models. Committee on Improving Risk Analysis Approaches Used by the U.S. EPA, National Research Council, Toward a Unified Approach to Dose–Response Assessment 127–87 (2009). Courts continue to grapple with the no-threshold model. See, e.g., In re W.R. Grace & Co. 355 B.R. 462, 476 (Bankr. D. Del. 2006) (the “no threshold model . . . flies in the face of the toxico- logical law of dose-response . . . doesn’t satisfy Daubert, and doesn’t stand up to scientific scrutiny”); Cano v. Everest Minerals Corp., 362 F. Supp. 2d 814, 853–54 (W.D. Tex. 2005) (even accepting the linear, no-threshold model for uranium mining and cancer, it is not enough to show exposure, you must show causation as well). Where administrative rulemaking is the issue, the no-threshold model has been accepted by some courts. See, e.g., Coalition for Reasonable Regulation of Naturally 643

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Reference Manual on Scientific Evidence in related disciplines (e.g., veterinary medicine, pharmacology, biochemistry, environmental health, or industrial hygiene). For a person with this type of back- ground, a single course in toxicology is unlikely to provide sufficient background for developing expertise in the field. A proposed expert should be able to demonstrate an understanding of the dis- cipline of toxicology, including statistics, toxicological research methods, and disease processes. A physician without particular training or experience in toxicology is unlikely to have sufficient background to evaluate the strengths and weaknesses of toxicological research. Most practicing physicians have little knowledge of environ- mental and occupational medicine.112 Generally, physicians are quite knowledgeable about the identification of effects and their treatment. The cause of these effects, particularly if they are unrelated to the treatment of the disease, is generally of little concern to the practicing physician. Subspecialty physicians may have particular knowledge of a cause-and-effect relationship (e.g., pulmonary physicians have knowledge of the relationship between asbestos exposure and asbestosis),113 but most physicians have little training in chemical toxicology and lack an understanding of exposure assessment and dose–response relationships. An exception is a physician who is certified in medical toxicology as a subspeciality under the American Board of Medical Specialties’ requirements, based on substantial training in toxicology and successful completion of rigorous examinations, including recertification exams.114 112. For recent documentation of how rarely an occupational history is obtained, see B.J. Politi et al., Occupational Medical History Taking: How Are Today’s Physicians Doing? A Cross-Sectional Investi- gation of the Frequency of Occupational History Taking by Physicians in a Major US Teaching Center. 46 J. Occup. Envtl. Med. 550–55 (2004). 113. See, e.g., Moore v. Ashland Chem., Inc., 126 F.3d 679, 701 (5th Cir. 1997) (treating physi- cian’s opinion admissible regarding causation of reactive airway disease); McCullock v. H.B. Fuller Co., 61 F.3d 1038, 1044 (2d Cir. 1995) (treating physician’s opinion admissible regarding the effect of fumes from hot-melt glue on the throat, where physician was board certified in otolaryngology and based his opinion on medical history and treatment, pathological studies, differential etiology, and scientific litera- ture); Benedi v. McNeil-P.P.C., Inc., 66 F.3d 1378, 1384 (4th Cir. 1995) (treating physician’s opinion admissible regarding the causation of liver failure by mixture of alcohol and acetaminophen, based on medical history, physical examination, laboratory and pathology data, and scientific literature—the same methodologies used daily in the diagnosis of patients); In re Ephedra Prods. Liab. Litig., 478 F. Supp. 2d 624, 633 (S.D.N.Y. 2007) (opinion of treating physician will assist the trier of fact because a reasonable juror would want to know what inferences a treating physician would make); Morin v. United States, 534 F. Supp. 2d 1179, 1185 (D. Nev. 2005) (treating physician does not have sufficient expertise to offer opinion about whether exposure to jet fuel caused cancer in his patient). Treating physicians also become involved in considering cause-and-effect relationships when they are asked whether a patient can return to a situation in which an exposure has occurred. The answer is obvious if the cause-and-effect relationship is clearly known. However, this relationship is often uncertain, and the physician must consider the appropriate advice. In such situations, the physician will tend to give advice as though the causality was established, both because it is appropriate caution and because of fears concerning medicolegal issues. 114. Before 1990, the American Board of Medical Toxicology certified physicians, but begin- ning in 1990, medical toxicology became a subspecialty board under the American Board of Emer- 676

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Reference Guide on Toxicology Some physicians who are occupational health specialists also have training in toxicology. Knowledge of toxicology is particularly strong among those who work in the chemical, petrochemical, and pharmaceutical industries, in which the surveillance of workers exposed to chemicals is a major responsibility. Of the occupational physicians practicing today, only about 1000 have successfully com- pleted the board examination in occupational medicine, which contains some questions about chemical toxicology.115 B. Has the Proposed Expert Been Certified by the American Board of Toxicology, Inc., or Does He or She Belong to a Professional Organization, Such as the Academy of Toxicological Sciences or the Society of Toxicology? As of January 2008, more than 2000 individuals had received board certification from the American Board of Toxicology. To sit for the examination, the candi- date must be involved full time in the practice of toxicology, including designing and managing toxicological experiments or interpreting results and translating them to identify and solve human and animal health problems. Diplomats must be recertified every 5 years. The Academy of Toxicological Sciences (aTs) was formed to provide credentials in toxicology through peer review only. It does not administer examinations for certification. Approximately 200 individuals are certified as Fellows of ATS. gency Medicine, the American Board of Pediatrics, and the American Board of Preventive Medicine, as recognized by the American Board of Medical Specialties. 115. Clinical ecologists, another group of physicians, have offered opinions regarding multiple chemical hypersensitivity and immune system responses to chemical exposures. These physicians generally have a background in the field of allergy, not toxicology, and their theoretical approach is derived in part from classic concepts of allergic responses and immunology. This theoretical approach has often led clinical ecologists to find cause-and-effect relationships or low-dose effects that are not generally accepted by toxicologists. Clinical ecologists often belong to the American Academy of Environmental Medicine. In 1991, the Council on Scientific Affairs of the American Medical Association concluded that until “accurate, reproducible, and well-controlled studies are available . . . multiple chemical sensitivity should not be considered a recognized clinical syndrome.” Council on Scientific Affairs, American Med. Ass’n, Council Report on Clinical Ecology 6 (1991). In Bradley v. Brown, 42 F.3d 434, 438 (7th Cir. 1994), the court considered the admissibility of an expert opinion based on clinical ecology theories. The court ruled the opinion inadmissible, finding that it was “hypothetical” and based on anecdotal evidence as opposed to scientific research. See also Kropp v. Maine School Adm. Union No. 44, 471 F. Supp. 2d 175, 181–82 (D. Me. 2007) (expert physician does not rely upon scientifically valid methodologies or data in reaching the conclusion that plaintiff is hypersensitive to phenol vapors in indoor air); Coffin v. Orkin Exterminating Co., 20 F. Supp. 2d 107, 110 (D. Me. 1998); Frank v. New York, 972 F. Supp. 130, 132 n.2 (N.D.N.Y. 1997). But see Elam v. Alcolac, Inc., 765 S.W.2d 42, 86 (Mo. Ct. App. 1988) (expert opinion based on clinical ecology theories admissible). 677

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Reference Manual on Scientific Evidence The Society of Toxicology (SOT), the major professional organization for the field of toxicology, was founded in 1961 and has grown dramatically in recent years. It now has 6300 members.116 Criteria for membership is based either on peer-reviewed publications or on the active practice of toxicology. Physician toxi- cologists can join the American College of Medical Toxicology and the American Academy of Clinical Toxicologists. There are also societies of forensic toxicology, such as the International Academy of Forensic Toxicology. Other organizations in the field are the American College of Toxicology, for which experience in the active practice of toxicology is the major membership criterion; the International Society of Regulatory Toxicology and Pharmacology; and the Society of Occu- pational and Environmental Health. For membership, the last two organizations require only the payment of dues. C. What Other Criteria Does the Proposed Expert Meet? The success of academic scientists in toxicology, as in other biomedical sciences, usually is measured by the following types of criteria: the quality and number of peer-reviewed publications, the ability to compete for research grants, service on scientific advisory panels, and university appointments. Publication of articles in peer-reviewed journals indicates an expertise in toxicology. The number of articles, their topics, and whether the individual is the principal or senior author are important factors in determining the expertise of a toxicologist.117 Most research grants from government agencies and private foundations are highly competitive. Successful competition for funding and publication of the research findings indicate competence in an area. Selection for local, national, and international regulatory advisory panels usually implies recognition in the field. Examples of such panels are the NIH Toxicology Study Section and panels convened by EPA, FDA, Who, and IARC. Recognized industrial organizations, including the American Petroleum Institute and the Electric Power Research Institute, and public interest groups, such as the Environmental Defense Fund and the Natural Resources Defense Council, 116. There are currently 21 specialty sections of SOT that represent the different specialty areas involved in understanding the wide range of toxic effects associated with exposure to chemical and physical agents. These sections include mechanisms, molecular biology, inhalation toxicology, metals, neurotoxicology, carcinogenesis, risk assessment, and immunotoxicology. 117. Examples of reputable, peer-reviewed journals are the Journal of Toxicology and Environmental Health; Toxicological Sciences; Toxicology and Applied Pharmacology; Science; British Journal of Industrial Medicine; Clinical Toxicology; Archives of Environmental Health; Journal of Occupational and Environmental Medicine; Annual Review of Pharmacology and Toxicology; Teratogenesis, Carcinogenesis and Mutagenesis; Fundamental and Applied Toxicology; Inhalation Toxicology; Biochemical Pharmacology; Toxicology Letters; Environmental Research; Environmental Health Perspectives; International Journal of Toxicology; Human and Experimental Toxicology; and American Journal of Industrial Medicine. 678

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Reference Guide on Toxicology employ toxicologists directly and as consultants and enlist academic toxicologists to serve on advisory panels. Because of a growing interest in environmental issues, the demand for scientific advice has outgrown the supply of available toxicologists. It is thus common for reputable toxicologists to serve on advisory panels. Finally, a university appointment in toxicology, risk assessment, or a related field signifies an expertise in that area, particularly if the university has a graduate education program in that area. VI. Acknowledgments The authors greatly appreciate the excellent research assistance provided by Eric Topor and Cody S. Lonning. 679

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Reference Manual on Scientific Evidence Glossary of Terms The following terms and definitions were adapted from a variety of sources, including Office of Technology Assessment, U.S. Congress, Reproductive Health Hazards in the Workplace (1985); Casarett and Doull’s Toxicology: The Basic Science of Poisons (Curtis D. Klaassen ed., 7th ed. 2007); National Research Council, Biologic Markers in Reproductive Toxicology (1989); Committee on Risk Assessment Methodology, National Research Council, Issues in Risk Assess- ment (1993); M. Alice Ottoboni, The Dose Makes the Poison: A Plain-Language Guide to Toxicology (2d ed. 1991); and Environmental and Occupational Health Sciences Institute, Glossary of Environment Health Terms (1989) [update]. absorption. The taking up of a chemical into the body orally, through inhalation, or through skin exposure. acute toxicity. An immediate toxic response following a single or short-term exposure to an agent or dosing. additive effect. When exposure to more than one toxic agent results in the same effect as would be predicted by the sum of the effects of exposure to the individual agents. antagonism. When exposure to one toxic agent causes a decrease in the effect produced by another toxic agent. benchmark dose. The benchmark dose is determined on the basis of dose– response modeling and is defined as the exposure associated with a specified low incidence of risk, generally in the range of 1% to 10%, of a health effect, or the dose associated with a specified measure or change of a biological effect. bioassay. A test for measuring the toxicity of an agent by exposing laboratory animals to the agent and observing the effects. biological monitoring. Measurement of toxic agents or the results of their metabolism in biological materials, such as blood, urine, expired air, or biopsied tissue, to test for exposure to the toxic agents, or the detection of physiological changes that are due to exposure to toxic agents. biologically plausible theory. A biological explanation for the relationship between exposure to an agent and adverse health outcomes. carcinogen. A chemical substance or other agent that causes cancer. carcinogenicity bioassay. Limited or long-term tests using laboratory animals to evaluate the potential carcinogenicity of an agent. chronic toxicity. A toxic response to long-term exposure or dosing with an agent. clinical ecologists. Physicians who believe that exposure to certain chemi- cal agents can result in damage to the immune system, causing multiple- 680

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Reference Guide on Toxicology chemical hypersensitivity and a variety of other disorders. Clinical ecologists often have a background in the field of allergy, not toxicology, and their theoretical approach is derived in part from classic concepts of allergic responses and immunology. There has been much resistance in the medical community to accepting their claims. clinical toxicology. The study and treatment of humans exposed to chemicals and the quantification of resulting adverse health effects. Clinical toxicology includes the application of pharmacological principles to the treatment of chemically exposed individuals and research on measures to enhance elimina- tion of toxic agents. compound. In chemistry, the combination of two or more different elements in definite proportions, which when combined acquire properties different from those of the original elements. confounding factors. Variables that are related to both exposure to a toxic agent and the outcome of the exposure. A confounding factor can obscure the relationship between the toxic agent and the adverse health outcome associated with that agent. differential diagnosis. A physician’s consideration of alternative diagnoses that may explain a patient’s condition. direct-acting agents. Agents that cause toxic effects without metabolic activa- tion or conversion. distribution. Movement of a toxic agent throughout the organ systems of the body (e.g., the liver, kidney, bone, fat, and central nervous system). The rate of distribution is usually determined by the blood flow through the organ and the ability of the chemical to pass through the cell membranes of the various tissues. dose, dosage. A product of both the concentration of a chemical or physical agent and the duration or frequency of exposure. dose–response curve. A graphic representation of the relationship between the dose of a chemical administered and the effect produced. dose–response relationships. The extent to which a living organism responds to specific doses of a toxic substance. The more time spent in contact with a toxic substance, or the higher the dose, the greater the organism’s response. For example, a small dose of carbon monoxide will cause drowsiness; a large dose can be fatal. epidemiology. The study of the occurrence and distribution of disease among people. Epidemiologists study groups of people to discover the cause of a disease, or where, when, and why disease occurs. epigenetic. Pertaining to nongenetic mechanisms by which certain agents cause diseases, such as cancer. 681

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Reference Manual on Scientific Evidence etiology. A branch of medical science concerned with the causation of diseases. excretion. The process by which toxicants are eliminated from the body, includ- ing through the kidney and urinary tract, the liver and biliary system, the fecal excretor, the lungs, sweat, saliva, and lactation. exposure. The intake into the body of a hazardous material. The main routes of exposure to substances are through the skin, mouth, and lungs. extrapolation. The process of estimating unknown values from known values. good laboratory practice (GLP). Codes developed by the federal government in consultation with the laboratory testing industry that govern many aspects of laboratory standards. hazard identification. In risk assessment, the qualitative analysis of all available experimental animal and human data to determine whether and at what dose an agent is likely to cause toxic effects. hydrogeologists, hydrologists. Scientists who specialize in the movement of ground and surface waters and the distribution and movement of contami- nants in those waters. immunotoxicology. A branch of toxicology concerned with the effects of toxic agents on the immune system. indirect-acting agents. Agents that require metabolic activation or conversion before they produce toxic effects in living organisms. inhalation toxicology. The study of the effect of toxic agents that are absorbed into the body through inhalation, including their effects on the respiratory system. in vitro. A research or testing methodology that uses living cells in an artificial or test tube system, or that is otherwise performed outside of a living organism. in vivo. A research or testing methodology that uses living organisms. lethal dose 50 (LD50). The dose at which 50% of laboratory animals die within days to weeks. lifetime bioassay. A bioassay in which doses of an agent are given to experi- mental animals throughout their lifetime. See bioassay. maximum tolerated dose (MTD). The highest dose of an agent to which an organism can be exposed without it causing death or significant overt toxicity. metabolism. The sum total of the biochemical reactions that a chemical produces in an organism. molecular toxicology. The study of how toxic agents interact with cellular molecules, including DNA. multiple-chemical hypersensitivity. A physical condition whereby individuals react to many different chemicals at extremely low exposure levels. 682

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Reference Guide on Toxicology multistage events. A model for understanding certain diseases, including some cancers, based on the postulate that more than one event is necessary for the onset of disease. mutagen. A substance that causes physical changes in chromosomes or bio- chemical changes in genes. mutagenesis. The process by which agents cause changes in chromosomes and genes. neurotoxicology. A branch of toxicology concerned with the effects of exposure to toxic agents on the central nervous system. no observable effect level (NOEL). The highest level of exposure to an agent at which no effect is observed. It is the experimental equivalent of a threshold. no-threshold model. A model for understanding disease causation that postulates that any exposure to a harmful chemical (such as a mutagen) may increase the risk of disease. one-hit theory. A theory of cancer risk in which each molecule of a chemical mutagen has a possibility, no matter how tiny, of mutating a gene in a manner that may lead to tumor formation or cancer. pharmacokinetics. A mathematical model that expresses the movement of a toxic agent through the organ systems of the body, including to the target organ and to its ultimate fate. potentiation. The process by which the addition of one agent, which by itself has no toxic effect, increases the toxicity of another agent when exposure to both agents occurs simultaneously. reproductive toxicology. The study of the effect of toxic agents on male and female reproductive systems, including sperm, ova, and offspring. risk assessment. The use of scientific evidence to estimate the likelihood of adverse effects on the health of individuals or populations from exposure to hazardous materials and conditions. risk characterization. The final step of risk assessment, which summarizes infor- mation about an agent and evaluates it in order to estimate the risks it poses. safety assessment. Toxicological research that tests the toxic potential of a chemi- cal in vivo or in vitro using standardized techniques required by governmental regulatory agencies or other organizations. structure–activity relationships (SAR). A method used by toxicologists to predict the toxicity of new chemicals by comparing their chemical structures with those of compounds with known toxic effects. synergistic effect. When two toxic agents acting together have an effect greater than that predicted by adding together their individual effects. target organ. The organ system that is affected by a particular toxic agent. 683

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Reference Manual on Scientific Evidence target-organ dose. The dose to the organ that is affected by a particular toxic agent. teratogen. An agent that changes eggs, sperm, or embryos, thereby increasing the risk of birth defects. teratogenic. The ability to produce birth defects. (Teratogenic effects do not pass to future generations.) See teratogen. threshold. The level above which effects will occur and below which no effects occur. See no observable effect level. toxic. Of, relating to, or caused by a poison—or a poison itself. toxic agent or toxicant. An agent or substance that causes disease or injury. toxicology. The science of the nature and effects of poisons, their detection, and the treatment of their effects. 684

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Reference Guide on Toxicology References on Toxicology A Textbook of Modern Toxicology (Ernest Hodgson ed., 4th ed. 2010). Casarett and Doull’s Toxicology: The Basic Science of Poisons (Curtis D. Klaas- sen ed., 7th ed. 2007). Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council, Toxicity Testing in the 21st Century: A Vision and a Strategy (2007). Environmental Toxicants (Morton Lippmann ed., 3d ed. 2009). Patricia Frank & M. Alice Ottoboni, The Dose Makes the Poison: A Plain- Language Guide to Toxicology (3d ed. 2011). Genetic Toxicology of Complex Mixtures (Michael D. Waters et al. eds., 1990). Human Risk Assessment: The Role of Animal Selection and Extrapolation (M. Val Roloff ed., 1987). In Vitro Toxicity Testing: Applications to Safety Evaluation (John M. Frazier ed., 1992). Michael A. Kamrin, Toxicology: A Primer on Toxicology Principles and Applica- tions (1988). Frank C. Lu, Basic Toxicology: Fundamentals, Target Organs, and Risk Assess- ment (4th ed. 2002). National Research Council, Biologic Markers in Reproductive Toxicology (1989). Alan Poole & George B. Leslie, A Practical Approach to Toxicological Investiga- tions (1989). Principles and Methods of Toxicology (A. Wallace Hayes ed., 5th ed. 2008). Joseph V. Rodricks, Calculated Risks (2d ed. 2006). Short-Term Toxicity Tests for Nongenotoxic Effects (Philippe Bourdeau et al. eds., 1990). Toxic Interactions (Robin S. Goldstein et al. eds., 1990). Toxic Substances and Human Risk: Principles of Data Interpretation (Robert G. Tardiff & Joseph V. Rodricks eds., 1987). Toxicology (Hans Marquardt et al. eds., 1999). Toxicology and Risk Assessment: Principles, Methods, and Applications (Anna M. Fan & Louis W. Chang eds., 1996). 685

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